The long-term goal of this project is to identify the genetic events that contribute to the development of relapsed and resistant acute promyelocytic leukemia (APL). We hypothesize that relapsed/resistant AML is associated with specific genetic events that can be defined with high throughput genome-wide scans for mutations. By mining the genetic information from humans and mice with relapsed and resistant APL, specific genes relevant for relapse and resistance will be discovered and validated. The identification of these target genes may lead to improved therapies for these patients. We propose the following Specific Aims: Specific Aim 1. We will generate and "bank" murine APL samples selected in vivo for resistance to ATRA, liposomal ATRA, or arsenic trioxide. We will demonstrate in vivo resistance by showing that survival of treated secondary recipients is not statistically different than the survival of recipients treated with diluent controls. We will also assess banked APL samples for resistance to ATRA or arsenic trioxide in vitro. We will incubate APL cells with these compounds for 24 hours and measure the expression of gelatinase B (which is expressed at its highest levels in terminally differentiated myeloid cells) using quantitative PCR. We will correlate in vitro and in vivo resistance. Specific Aim 2. We will identify candidate loci associated with APL resistance using RNA profiling and comparative genomic hybridization (CGH) techniques. The samples generated in Aim 1 will be subjected to genome wide scans for alterations in gene expression, and for regions of chromosomal amplifications or losses using high resolution CGH. We will also compare paired RNA profiles from human APL patients with de novo vs relapsed and/or resistant disease. Specific Aim 3. We will resequence the exons of candidate genes that have been associated with the development of resistance. Candidate murine and human loci identified in Aim 2 will be resequenced in de novo and resistant APL samples. The approximately 450 leukemia-associated genes in Projects 1 and 4 will also be resequenced in a limited number of paired samples from patients with de novo vs. resistant disease.